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Division of Cardiology, Department of Medicine, University of Minnesota Medical School, Minneapolis 55455; and Minneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis, Minnesota 55407
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Coronary blood flow (CBF) and myocardial
oxygen consumption (M
O2) are reduced
in dogs with pacing-induced congestive heart failure (CHF), which
suggests that energy metabolism is downregulated. Because nitric oxide
(NO) can inhibit mitochondrial respiration, we examined the effects of
NO inhibition on CBF and MO2 in dogs with CHF. CBF and MO2 were measured
at rest and during treadmill exercise in 10 dogs with CHF produced by
rapid ventricular pacing before and after inhibition of NO production
with NG-nitro-L-arginine
(L-NNA, 10 mg/kg iv). The development of CHF was
accompanied by decreases in aortic and left ventricular (LV) systolic
pressure and an increase in LV end-diastolic pressure (25 ± 2 mmHg). L-NNA increased
MO2 at rest (from 3.07 ± 0.61 to 4.15 ± 0.80 ml/min) and during exercise; this was accompanied by an increase in CBF at rest (from 31 ± 2 to 40 ± 4 ml/min) and during exercise (both P < 0.05). Although
L-NNA significantly increased LV systolic pressure, similar
increases in pressure produced by phenylephrine did not increase
MO2. The findings suggest that NO
exerts tonic inhibition on respiration in the failing heart.
nitric oxide; synthase; exercise
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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RECENT EVIDENCE
SUGGESTS that endogenous nitric oxide (NO) can inhibit
mitochondrial respiration in a variety of tissues including skeletal
muscle (22) and cardiac myocytes (3). In
isolated mitochondria, NO reversibly inhibits respiration by competing with oxygen at the Fe/Cu centers of cytochrome oxidase
(4). In isolated heart preparations, the addition of
authentic NO (20) or endothelium-dependent agonists such
as bradykinin (25) significantly decreased oxygen
consumption (MO2) and
myocardial contractility. Conversely, inhibition of NO production with
competitive antagonists of NO synthase (NOS) resulted in significant
increases in whole body oxygen consumption (29) and small
but significant increases of MO2 and
coronary blood flow (CBF) in normal dogs (1, 15).
In dogs with pacing-induced congestive heart failure (CHF), we observed
that CBF and MO2 were significantly
decreased at rest and during exercise compared with normal animals
(32). Insufficient oxygen delivery did not appear to be a
limiting factor in the reduced oxygen uptake, because oxygen extraction
was not increased and coronary sinus PO2 was
not different from normal. This suggested that energy utilization and
therefore oxygen demand is depressed in the failing heart. Because of
the known effects of NO in depressing mitochondrial respiration, we
undertook the present study to determine whether endogenous NO inhibits
MO2 and CBF at rest and during
exercise in dogs with pacing-induced CHF. The
MO2 and CBF responses were compared
to a group of normal dogs previously studied in our laboratory
(1).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Studies were carried out on 10 adult mongrel dogs (body wt 25-30 kg) in accordance with the position of the American Heart Association on research animal use and were approved by the Animal Care Committee of the University of Minnesota.
Surgical preparation. Animals were anesthetized with pentobarbital sodium (30-35 mg/kg iv), intubated, and ventilated with oxygen-enriched room air. A left thoracotomy was performed and heparin-filled polyvinyl catheters (3.0 mm OD) were introduced into the ascending aorta and the left atrium. A similar catheter was advanced through the right atrium into the coronary sinus and positioned in the great cardiac vein to drain venous blood from the distribution of the left anterior descending coronary artery (LAD). A fluid-filled catheter and Konigsberg micromanometer were introduced into the left ventricle at the apex. A Doppler velocity probe was placed around the proximal LAD, and a heparin-filled silicone-rubber catheter (0.3 mm ID) was placed into the artery. An epicardial pacing lead was screwed into the right ventricle. The pericardium was loosely closed, the catheters and electrical leads were tunneled subcutaneously to exit at the base of the neck, and the thoracotomy was repaired. A programmable pacing generator (Medtronic model 5385; Minneapolis, MN) was placed in a subcutaneous pocket and connected to the pacing lead.
Production of heart failure. One week after surgery, the pacemaker was activated at 220 beats/min and continued at that rate or increased up to 250 beats/min until CHF had developed. Weekly assessments of hemodynamics and CBF were obtained with the dogs standing quietly in a sling in sinus rhythm 1 h after the pacemaker had been deactivated. CHF was deemed to have developed when the resting left ventricular (LV) end-diastolic pressure (LVEDP) was >20 mmHg or when the visual estimation of ejection fraction by echocardiography was <25%.
Effects of
NG-nitro-L-arginine on
CBF and
MO2.
On the day of the study, the pacemaker was deactivated and the dog was
placed on the treadmill. Resting hemodynamic and CBF measurements were
obtained 1 h after pacemaker deactivation. Aortic and coronary
venous blood samples (3 ml) were withdrawn and placed on ice for
determination of oxygen content. The treadmill was then started at 3.2 km/h and 0% grade. After 3 min of exercise, aortic and coronary venous
blood samples were again withdrawn for blood gas
measurements. For six dogs, the treadmill speed was increased to 6.4 km/h; after 3 min, hemodynamic measurements and blood samples were
again obtained. During the first exercise stage, radioactive
microspheres were injected through the left atrial catheter
(n = 9) to determine the transmural distribution of
myocardial blood flow. After a 1-h rest period,
NG-nitro-L-arginine
(L-NNA, 10 mg/kg) was infused through the left atrial
catheter to inhibit NO production. All resting and exercise measurements were repeated 1 h later.
Determination of
MO2.
Blood oxygen content was determined with a blood gas analyzer
(Instrumentation Laboratory model 113). Blood oxygen content (in
milliliters per 100 milliliters of blood) was calculated as (0.0136 × hemoglobin × % oxygen saturation) + (PO2 × 0.0031). MO2 in the LAD distribution was
calculated as the arteriovenous difference of oxygen content multiplied
by CBF.
Determination of myocardial blood flow. Myocardial blood flow was measured with radioactive microspheres in nine animals during the first stage of exercise before and after L-NNA. For each measurement, 3 × 106 microspheres (15 µM diameter) were injected through the left atrial catheter. After completion of exercise, the animals were euthanized with pentobarbital sodium. Myocardial specimens were removed from the anterior and posterior regions of the left ventricle, sectioned into four layers from epicardium to endocardium, weighed, and placed into vials for counting.
Effect of L-NNA administration on responses to endothelium-dependent agonist. To assess the ability of L-NNA to inhibit NO-mediated vasodilation, CBF responses to ACh were measured before and after L-NNA administration in three animals with CHF. ACh dissolved in normal saline was infused through the LAD catheter at rates of 3.75-37.5 µg/min (0.15-1.5 ml/min). L-NNA (10 mg/kg iv) was then administered through the left atrial catheter and the responses to ACh were repeated 1 h later.
Effects of phenylephrine on CBF and
MO2.
L-NNA administration resulted in a significant increase in
mean aortic pressure that might have increased CBF and
MO2 independent of NO inhibition.
Consequently, in four dogs with CHF, measurements of CBF and
MO2 were performed while the animals
stood quietly in a sling before and after administration of the
-adrenergic agonist phenylephrine in a dose (8 µg · kg
1 · min1 iv) that
caused an increase in aortic pressure at least as great as that
produced by L-NNA infusion.
Data analysis. Heart rate, pressures, and coronary velocity were measured from the strip-chart recordings. LAD flow was calculated from the Doppler frequency shift as previously described (16). Data were compared using two-way ANOVA for repeated measures (exercise level and treatment); a value of P < 0.05 was required for statistical significance. When a significant result was found, individual comparisons were performed with the Tukey or Wilcoxon signed-rank test. Data are expressed as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Control hemodynamics and
MO2.
After the development of CHF, resting mean aortic pressure was 89 ± 3 mmHg, mean heart rate was 140 ± 4 beats/min, LVEDP was 25 ± 2 mmHg, and LAD CBF was 31 ± 2 ml/min (Table
1). Exercise resulted in significant progressive
increases in heart rate, aortic pressure, and LV systolic pressure. CBF
increased to 37 ± 3 ml/min during exercise stage
1 (n = 10; P < 0.01) and to
44 ± 4 ml/min during exercise stage 2 (n = 8; P < 0.05). Resting
MO2 was 3.1 ± 0.6 ml
O2/min and progressively increased with each stage of exercise (Table 2). Coronary sinus
PO2 was 23 ± 2 mmHg at rest and decreased
to 18 ± 2 mmHg during exercise stage 1 (P < 0.05) with no further change during
exercise stage 2.
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Hemodynamics and MO2 after
L-NNA administration.
L-NNA infusion significantly increased resting mean aortic
and LV systolic pressure (see Table 1). Heart rate tended to decrease, but this was not significant. Resting CBF after L-NNA
administration was 30 ± 8% higher than during control conditions
at a similar rate-pressure product. Similarly, CBF was
significantly higher than control during each exercise stage after
L-NNA administration (Fig.
1).
MO2 was significantly greater after
L-NNA infusion at rest and during the first stage of
exercise compared with control and tended to be greater during
exercise stage 2, although this did not achieve statistical
significance (Fig. 2). Coronary venous PO2 tended to be lower after L-NNA
administration, which reflects an increase in oxygen extraction.
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Transmural myocardial blood flow. Subendocardial and subepicardial blood flow and its ratio (endo/epi) was measured with microspheres in nine dogs during the first stage of exercise before and after L-NNA infusion. During control exercise, the endo/epi flow ratio was 1.34 ± 0.15; this was unchanged during exercise with L-NNA (1.42 ± 0.18).
Effect of L-NNA on responses to
endothelium-dependent agonist.
During control conditions, intracoronary ACh progressively increased
CBF with no significant change in systemic hemodynamics (Fig.
3). L-NNA administration (10 mg/kg iv) resulted in 50-70% inhibition of the increase in CBF
produced by ACh.
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Effects of phenylephrine on CBF and
MO2.
In four dogs with CHF, phenylephrine increased LV systolic pressure
from 87 ± 2 to 116 ± 7 mmHg (P < 0.05)
while heart rate decreased from 112 ± 6 to 100 ± 3 beats/min. There was no change in CBF (22 ± 4 vs. 21 ± 3 ml/min) or MO2 (2.0 ± 0.3 vs.
2.0 ± 0.7 ml O2/min) during phenylephrine infusion.
These results suggest that the increase in CBF and
MO2 produced by L-NNA
administration was specific to NO inhibition and was not the result of
the increase in LV systolic pressure that was produced by
L-NNA.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, we report for the first time the in vivo effects of
NO inhibition on MO2 and CBF at rest
and during exercise in the failing heart. The results demonstrate that
inhibition of NO production with L-NNA caused significant
increases of CBF and MO2 and that
these effects could not be explained by the increase in LV systolic
pressure that is produced by this agent.
Effects of NO on mitochondrial respiration in the
normal heart.
Borutaite and Brown (3) demonstrated that NO caused
reversible inhibition of oxygen consumption in mitochondria isolated from rat hearts. Furthermore, they showed that the rate of oxygen consumption varied with the local NO/oxygen ratio, thus supporting the
concept that competitive inhibition exists between NO and oxygen at the
level of cytochrome oxidase and that this occurs at physiological
concentrations (4). Similarly,
NG-nitro-L-arginine methyl ester
increased oxygen consumption of isolated porcine aortic endothelial
cells whereas the receptor-mediated production of NO (bradykinin)
significantly reduced respiration (5). In isolated
guinea pig hearts, Kelm et al. (20) observed that NO
concentrations of 10 nM to 1 µM increased CBF and cGMP without
changing LV developed pressure or
MO2. However, at a concentration of
100 µM, NO caused reversible decreases of LV developed pressure and
dP/dt (first derivative of LV pressure) as well as a 60%
decrease in MO2. This was
accompanied by significant decreases of ATP and phosphocreatine, which
suggests that high levels of NO can impair contractile performance by
depressing myocardial ATP production in a reversible, dose-dependent manner.
O2 during treadmill
exercise, but this was associated with a small but significant increase
in rate-pressure product that could have contributed to the increase in
MO2 (1, 15). Using a
lower dose of L-NNA (1.5 mg/kg intracoronary) which did not
cause an increase in blood pressure, Ishibashi et al. (15)
demonstrated that NOS blockade increased
MO2 during heavy treadmill
exercise at rate-pressure products that were similar to control. The
findings imply that NOS blockade results in an increase of
MO2 out of proportion to any
increase in cardiac work that it may produce.
Effect of NO on
MO2 in the failing
heart.
In a previous study using this experimental model (32), we
observed that the development of CHF was accompanied by significant decreases of resting CBF and MO2,
and that CBF and MO2 failed to
increase normally with increasing levels of exercise. The oxygen supply
to the failing myocardium did not appear to be a limiting factor,
because oxygen extraction did not increase and coronary venous
PO2 did not differ from control. To determine
whether an increase of external cardiac work produced by NOS inhibition
could account for the increases of CBF and
MO2 that were observed after
L-NNA administration, in the present study we examined the response of MO2 to
phenylephrine-induced increases of blood pressure. Increases in LV
systolic pressure produced by phenylephrine did not increase
MO2 or CBF. Thus the increased
MO2 produced by L-NNA
infusion in the present study could not be ascribed to the increase in
LV systolic pressure that it produced. Although our study cannot
exclude other effects of L-NNA on internal efficiency, catecholamine responsiveness, or substrate selectivity, the results suggest that endogenous NO exerts some degree of tonic inhibition on
MO2 in the failing heart.
O2 and rate-pressure
product. The increase in MO2 after L-NNA administration was accompanied by a significant
increase in the arteriovenous oxygen difference, which indicates that
the failing myocardium was able to increase oxygen extraction. However, there was no further increase in oxygen extraction with exercise, so that the increase in MO2 during
exercise after L-NNA infusion resulted solely from
the increased CBF. Thus the increase in oxygen usage secondary to
disinhibition of NO effects on respiration was maximal at rest, so that
no further increase in oxygen extraction occurred during exercise.
The apparent role for NO in the failing heart is surprising given
previous reports that endothelium-dependent NO production and
NO-mediated vasodilation are impaired in the peripheral (8, 17,
22) and coronary circulation with CHF (13, 33).
Kaiser et al. (17) observed that femoral artery
vasodilation to topical ACh was reduced in dogs with pacing-induced CHF
whereas responses to nitroglycerine were unchanged compared to normal.
Elsner et al. (8), using a similar model of CHF, observed
no significant increase in systemic vascular resistance after NO
inhibition with L-NNA (5 mg/kg iv), which suggests that NO
production is reduced in the peripheral vasculature in heart failure.
In contrast, using a higher dose of L-NNA (10 mg/kg), we
observed a significant increase in arterial pressure, although we did
not measure systemic vascular resistance. Wang et al. (33)
observed that the oxidative products of NO (NOx) produced by isolated
coronary microvessels in response to endothelium-dependent vasodilators
was decreased in dogs with pacing-induced CHF compared to normal dogs.
Katz et al. (19), using infusions of
L-[15N]arginine, observed that the 24-h
excretion of [15N]nitrate was reduced in patients with
CHF, which suggests decreased activity of the L-arginine/NO
pathway. In contrast, several studies suggest that NO activity is
increased in CHF or that basal NO production is maintained whereas
agonist-mediated NO production is diminished (2, 7). In
myocardium taken from explanted human hearts during transplantation,
Loke et al. (23) reported that the endothelium-dependent
agonist bradykinin decreased oxygen consumption up to 21% in a
dose-dependent manner, which supports an effect of endothelium-derived
NO on respiration in failing hearts.
Drexler et al. (7) demonstrated that the decrease in
forearm blood flow in response to
NG-monomethyl-L-arginine
administration was enhanced in patients with CHF, which suggests
increased basal NO production. In aortic rings from rats with CHF 8 wk
after left coronary artery ligation, Bauersachs et al. (2)
observed impaired relaxation in response to ACh, which suggests the
development of endothelial dysfunction. Interestingly, these animals
demonstrated upregulation of endothelial NOS (eNOS) and soluble
guanylate cyclase but reduced formation of cGMP in response to sodium
nitroprusside, which the investigators attributed to enhanced
NADH-dependent vascular superoxide anion (O
are reported to be increased in patients with CHF and can
result in induction of inducible NOS (iNOS) expression in cardiac
myocytes and vascular smooth muscle (12). Haywood et al.
(14) demonstrated that iNOS was expressed in parallel with
ANP in explanted hearts from patients undergoing cardiac transplantation with no expression in normal ventricles. Similar findings were reported by Habib et al. (12) using
immunohistochemistry on myocardial biopsy specimens from patients with
dilated cardiomyopathy. Previous reports employing the model used in
this study have failed to demonstrate significant iNOS in myocardial
tissue (13, 21) and cytokine levels are not increased with
the development of pacing-induced CHF (26). We observed
only a faint iNOS band on Western analysis of myocardial tissue from
the failing ventricles of the animals in this study. However, because
of the high NO output of iNOS, even modest expression of this protein
might account for significant NO production in the failing heart. An
additional possible mechanism for the increased
MO2 after L-NNA
administration relates to reports that NO inhibits 
-adrenergic
responsiveness in failing hearts but not in normal hearts (13,
31). Because exercise is associated with sympathetic activation,
inhibition of NO production might augment -adrenergic effects on
myocardial contractility and coronary resistance vessel dilation.
Recently, an isoform of NOS localized to the inner mitochondrial
membrane has been reported (10, 11) and identified as
neuronal NOS (18). Although NO production by the
mitochondria has been reported not to be a significant source of NO in
the normal heart (9), this isoform is overexpressed in
dysfunctional cardiomyocytes from dystrophin knockout mice that are
deficient in caveolar NOS (eNOS) (18). NO production by
mitochondria-associated NOS has not been studied in failing myocardium
produced by rapid ventricular pacing. Because L-NNA used in
the present study causes nonselective inhibition of NOS activity, we
cannot determine the contribution of the individual isoforms to our results.
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ACKNOWLEDGEMENTS |
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The authors acknowledge the expert technical assistance provided by Paul Lindstrom, Melanie Crampton, and Shauna Voss. Secretarial assistance was provided by Carol Quirt.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grants HL-20598, HL-21872, and HL-58067. J. H. Traverse was supported by a Scientist Development Grant from the American Heart Association.
Address for reprint requests and other correspondence: R. J. Bache, Division of Cardiology, Dept. of Medicine, Univ. of Minnesota Medical School, Mayo Mail Code 508 UMHC, 420 Delaware St. SE, Minneapolis, MN 55455 (E-mail: bache001{at}tc.umn.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00504.2001
Received 8 June 2001; accepted in final form 23 January 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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